Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Claims 1-20 were filed on 31 July 2023. Currently, claims 1-20 are being considered.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 29 September 2023 was filed after the mailing date of the effective filing date on 31 July 2023. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Specification
The use of the term Fintepla (para. 3), Triton X-100 (para. 26), TPGS-750-M (para. 26, Table 2), Spans (para. 26), Span80 (Table 2), Tweens (para. 26), and Tween60 (Table 2) which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore, the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 12 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The term “substantially” in claim 12 is a relative term which renders the claim indefinite. The term “substantially” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The quality or composition of the water as disclosed in the claim has been rendered indefinite as the undefined termed “substantially” does not define the metes and bounds of the water used.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-2, 4-8, 11, and 13-21 are rejected under 35 U.S.C. 103 as being unpatentable over Londesbrough et al. (Fenfluramine compositions and methods of preparing the same, WO 2017/112702 A1, IDS entered on date 29 August 2023) in view of Thakore (Chemoselective reduction amination in aqueous nanoreactors using parts per million level Pd/C catalysis, Org. Lett. 2020, 22, 6324-6329, IDS entered on 29 August 2023).
Londesbrough discloses:
The preparation of fenfluramine from 1-(3-(trifluoromethyl)phenyl)-propan-2-one by reductive amination with ethylamine through formation of the imine intermediate between the ketone and amine followed by hydride reduction using sodium triacetoxyborohydride in a methanol/water solution (para. 32-34).
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Londesbrough also discloses the preparation of fenfluramine free base into its hydrochloride salt, performing purity analysis by HPLC, and preparation of fenfluramine salts with another pharmaceutically acceptable excipient.
Londesbrough does not, however, disclose, the use of a heterogenous light platinum-group metal catalyst and a hydrosilane.
Thakore discloses:
Palladium over carbon (Pd/C) at 0.2 mol% Pd loading, catalyzed reductive aminations optimally utilizing triethylsilane but also screened phenylsilane, phenylmethylsilane, diphenylsilane, etc., reacted in water between carbonyl containing compounds and amines, localized to the hydrophobic cores of nano-micelles formed from a non-ionic surfactant (TPGS-750-M) that demonstratively reduces the required catalyst loading when compared to reactions with no surfactant (metal catalyst 2-10 mol% loading) and high yielding product generation (>83% yield) (abstract). This approach is applied chemoselectively to several types of pharmaceuticals, at scale, and in a tandem reaction environment.
Claim 4-8 are rejected under 35 U.S.C. 103 as being unpatentable over Londesbrough and Thakore as the limitations of claims 4-7 are inherently met. Claim 4, depending on claim 1, further limits the claims by specifying a catalyst that is palladium supported on carbon (Pd/C), which is rejected by Thakore. Claim 5, depending on claim 4, further limits the claim by specifying the palladium catalyst loading, with respect to 3-(trifluoromethyl)phenylacetone to ranges from about 0.2 mol% and about 1 mol%, with about being defined in the specification as a variation of ±0.1 moles, which is rejected by Thakore utilizing 0.2 mol% in the described reaction conditions. Claim 6, depending on claim 1, further limits the claim by specifying the hydrosilane to be selected from a group consisting of triethylsilane, phenyl silane, phenylmethyl silane, diphenyl silane, and polymethylhydrogensiloxane. This is rejected by Thakore, illustrated in Table 1, where the reducing reaction conditions were optimized through variation of the previously described hydrosilanes and other reducing agents. Claim 7, depending on claim 1, further limits the claim by specifying the hydrosilane to be triethylsilane, which is rejected by Thakore. Claim 8, depending on claim 7, further limits the claim by specifying that the surfactant is a non-ionic surfactant or an anionic surfactant, which is also rejected by Thakore. Claim 11, depending on claim 8, further limits the claim by specifying that the amount of surfactant used with respect to 3-(trifluoromethyl)phenylacetone ranges from about 1 wt.% and about 5 wt.%, which is rejected by Thakore. Claim 13, depending on claim 1, further limits the claim by specifying that the reaction is conducted in a sealed vessel at a temperature ranging from about 20 °C to about 100 °C. This is rejected by Thakore, who describes conducting reactions in sealed single dram vials with reaction temperatures of 45 °C and 55 °C for aldehyde and ketone substrates, respectively. Claims 14-16, with claims 14 and 16 depending on claim 1, and claim 15 depending on claim 14, further limit the claim by further converting fenfluramine to a pharmaceutically acceptable salt, which is rejected by Londesbrough who describes the conversion of free base fenfluramine into the pharmaceutically acceptable hydrochloride (HCl) salt. This process is described as a telescoped process, where the formation of the fenfluramine HCl salt is generated in-situ. Claims 17-19, depending on claim 16, further limits the claims by specifying the produced quantity of impurity 1-[3-(trifluoromethyl)phenyl]-2-propanol, as determined by HPLC analysis, to 0.2%, 0.1%, and 0.05% area of the spectral integrated area, which is rejected by Londesbrough that observes no cGMP batch that exceeds any impurity quantity of over 0.15% as determined by HPLC (Table 8). Claim 20, depending on claim 16, further limits the claim by specifying a limit of no more than 10 ppm of catalyst metal impurities with respect to fenfluramine, which is rejected by Thakore, that observes less than 1 ppm of Pd as determined by ICP-MS (Thakore, pg. 6326). Claim 21, depending on claim 16, further limits the claim by specifying a pharmaceutical composition of fenfluramine or a salt thereof and one or more pharmaceutically acceptable excipients, which is rejected by Londesbrough.
As such, it would have been prima facie obvious to a person of ordinary skill in the art, before the effective filing date, to apply a similar reductive amination approach, as taught by Thakore, to the synthesis of fenfluramine as disclosed by Londesbrough.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Londesbrough and Thakore as applied to claims 1-2 above, and further in view of Braga (Synthesis of fentanyl under continuous photoflow conditions, Org. Lett. 2022, 24, 8331-8336).
The teachings of Londesbrough and Thakore are set forth and incorporated herein by reference.
Londesbrough and Thakore do not disclose the use of a ruthenium catalyst.
Braga teaches a telescoped, two intermediate steps in the synthesis of fentanyl through a ruthenium photoredox catalyzed reductive amination, first between 4-aminohexacyclo-1-one and benzylaldehyde, and then between the ketone adduct and aniline to give the penultimate secondary amine adduct. This synthesis of an active pharmaceutical ingredient demonstrates an efficient, light-driven catalytic, and functionally scalable reductive amination that closely parallels the synthesis of fenfluramine.
As such, it would have been prima facie obvious to a person of ordinary skill in the art, before the effective filing date, to apply the use of ruthenium or Ru/C for the synthesis of fenfluramine as described by Londesbrough, as an effective alternative to Pd/C as a catalyst, taught by Braga as a scalable, heterogenous, and specifically light platinum-group metal catalyst, which is a property specified in claim 1 but is not further expanded upon by the use of Pd/C in the claims or in the specifications including the provided examples.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Londesbrough and Thakore as applied to claims 1-2, 4-8, 11, and 13-21 above, and further in view of Shen et al. (Recent advances on micellar catalysis in water, Adv. Colloid and Interface Sci., 2021, 287, 102299).
The teachings of Londesbrough and Thakore are set forth and incorporated herein by reference.
Londesbrough and Thakore do not disclose where the surfactant is an anionic surfactant, consisting of carboxylic acids, carboxylate salts, sulfate salts, and phosphate salts.
This deficiency is resolved by the teachings of Shen, which discloses: anionic surfactants which are bi-domain molecules with a linear aliphatic chain and anionic group head, aggregating in solution with oppositely charged ionic surfactant to form anionic micelles. Common anionic surfactants are disclosed to be sodium dodecyl sulfate (SDS) and oleic acid. Shen notes an advantage of anionic micelles over cationic micelles through the capacity to bind on the micellar surface a positively charged active metal species and spatially confining insoluble organic reagents within the micellar core, resulting in empirical examples of improved reaction rates.
As such, it would have been prima facie obvious to a person of ordinary skill in the art, before the effective filing date, to explore the utility of micelles constructed from anionic surfactants as there are many other palladium catalysts aside from Pd/C that are known in the literature with positively charged oxidation states, including +2 and +4. As taught by Shen, using anionic surfactants should be a consideration when screening these cationic catalysts to further optimize the reductive amination step of fenfluramine synthesis.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Londesbrough, Thakore, and Shen, as applied to claim 9 above, and in further view of Hong et al. (Multi-responsive emulsion of stearic acid soap aqueous solution, Colloids and Surfaces A: Physicochemical and Engineering Aspects, 2017, 522, 652-657) and Debnath (Micelles and reverse micelles: a fascinating micro-reactor, Modern Approaches in Chemical and Biological Sciences Vol-2, 2022, 17-23)
The teachings of Londesbrough, Thakore, and Shen are set forth and incorporated herein by reference.
Londesbrough, Thakore, and Shen do not disclose the use of stearic acid or salt thereof.
This is remedied by the teachings of Hong, which describes the formation of various aggregates and structures of stearic acid as a type of anionic surfactant capable of forming micelles. Hong describes fatty acids, in which stearic acid falls under, as a biocompatible anionic surfactant which exists in nature and is a cheap resource from the oils of both animals and plants. While exploring several empirical parameters, Hong observes the formation of micelles from stearic acid when the pH is considerably higher than the pKa. Debnath notes the use of other anionic surfactants similar to stearic acid are also capable of forming micelles and being used as so-called microreactors, capable of increasing the rates of reactions up to 10-100 fold, and applicable to a wide variety of chemical transformations including ester hydrolysis, Diels-Alder, sulfoxidations, among others.
As such, it would have been prima facie obvious to a person of ordinary skill in the art, before the effective filing date, to consider the use of stearic acid and salts thereof as a candidate for forming anionic micelles due to their non-toxic and cheap commercial availability and the application of other anionic surfactants as micelle chemical reactors demonstratively capable of a varied breadth of chemical transformations.
Claim 22, is rejected by 35 U.S.C. 103 as being unpatentable over Londesbrough and Thakore, as applied to claim 21 above, and in further view of Crowley (Solutions, emulsions, suspensions, and extracts, Remington the science and practice of pharmacy, 21st edition, chapter 39, copyright 2006, IDS entered on 29 August 2023).
The teachings of Londesbrough and Thakore are set forth and incorporated herein by reference.
Londesbrough and Thakore do not disclose the use of a pharmaceutical composition as an oral solution.
Crowley addresses this deficiency by describing the preparation of pharmaceutical compositions in orally deliverable gels, pharmaceutical dosage forms, aqueous solutions including aromatics, juices, and their preparations. Active pharmaceutical ingredients are generally not in an appropriate form to be easily delivered as a product due to a combination of considerations including chemical and physical stability outside and inside the human body, the resulting pharmaco-kinetics and dynamics, taste to the recipient, etc. Fenfluramine hydrochloride salt, from a structural observation, may have poor water solubilizing properties and would need to be formulated for use to both optimize the physiological outcome and also to address the previous considerations. The preparation of these dosage forms also requires several considerations on the part of the pharmacist, including purpose of the drug, selection of the liquid vehicle, physical and chemical stability of the drug and any excipients, preservation of the preparation, and appropriate use of excipients such as buffers, solubility enhancers, suspending agents, emulsifying agents, viscosity controlling agents, colors and flavors.
As such, it would have been prima facie obvious to a person of ordinary skill in the art, before the effective filing date, to consider oral solutions or other formulations as taught by Crowley as a delivery mechanism for the fenfluramine pharmaceutical composition to be efficacious and palatable to the patient.
Conclusion
No claims are allowable.
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/ALLEN CHAO/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622